For implanting orthopaedic or dental implants, generally metallic implants, into bone tissue, a one-stage procedure is nowadays often used.
In the one-stage procedure, a first implant part, such as a dental fixture, is generally surgically placed into the bone tissue, and a healing cap or a secondary implant part, such as an abutment, is then attached to the first implant part directly after the surgical operation. The soft tissue is then allowed to heal around the healing cap or the secondary implant part. When a healing cap is used, the cap is removed after a few weeks or months without any surgical procedure, and secondary implant parts, such as an abutment and a provisional crown, are attached to the first implant part. The one-stage proce-dure is for instance described in L Cooper et al: “A multicenter 12-month evaluation of single-tooth implants restored 3 weeks after 1-stage surgery”, The International Journal of Oral & Maxillofacial Implants, Vol 16, No 2 (2001).
The two-stage procedure, which in some dental cases still is preferable, generally involves in a first stage surgically placing a first implant part, such as a dental fixture, into the bone tissue, where it is allowed to rest unloaded and immobile for a healing period, often of three months or more, in order to allow the bone tissue to grow onto the implant surface to permit the implant to be well attached to the bone tissue, the cut in the soft tissue covering the implant site being allowed to heal over the implant. In a second stage, the soft tissue covering the implant is opened and secondary implant parts, such as a dental abutment and/or a restoration tooth, are attached to the first implant part, such as said fixture, forming the final implant structure. This procedure is for instance described by Brånemark et al: “Osseointegrated Implants in the Treatment of the Edentulous Jaw, Experience from a 10-year period”, Almquist & Wiksell International., Stockholm, Sweden.
However, the fact that the implant not should be loaded during the healing period means that the secondary implant parts may not be attached to the first implant part and/or used during the healing period. In view of the discomfort associated with this, it is desirable to minimize the time period necessary for the above-mentioned first stage or even perform the entire implantation procedure in a single operation, i.e. to use the one-stage procedure.
For some patients, it might be considered better to wait at least three months before functionally loading the implant, both for one- and two-stage procedures. However, an alternative using the one-stage procedure is to put the implant in function directly after implantation (immediate loading) or a few weeks after implantation (early loading). These procedures are, for instance, described by D M Esposito, pp 836-837, in “Titanium in Medicine, Material Science, Surface Science, Engineering, Biological Responses and Medical Application”, Springer-Verlag (2001).
It is essential that the implant establishes a sufficient stability and bond between implant and bone tissue to enable the above disclosed immediate or early loading of the implant. It shall also be noted that an immediate or early loading of the implant may be beneficial to bone formation.
Some of the metals or alloys, such as titanium, zirconium, hafnium, tantalum, niobium, or alloys thereof, that are used for bone implants are capable of forming a relatively strong bond with the bone tissue, a bond which may be as strong as the bone tissue per se, and sometimes even stronger. The most notable example of this kind of metallic implant material is titanium and alloys of titanium whose properties in this respect have been known since about 1950. The bond between the metal and the bone tissue has been termed “osseointegration” (Albrektsson T, Brånemark P I, Hansson H A, Lindström J, “Osseointegrated titanium implants. Requirements for ensuring a long-lasting, direct bone anchorage in man”, Acta Orthop Scand, 52:155-170 (1981)).
It may be noted that in contact with oxygen, titanium, zirconium, hafnium, tantalum, niobium and their alloys are instantaneously covered with a native oxide. This native oxide on titanium implants mainly consist of titanium(IV) dioxide (TiO2) with minor amounts of Ti2O3, TiO and Ti3O4.
Although the bond between the (oxidised) metal., e.g. titanium, and the bone tissue may be comparatively strong, it is desirable to enhance this bond.
There are to date several methods for treating metallic implants in order to obtain a better attachment of the implant, and thus improved osseointegration. Some of these involve altering the morphology of the implant, for example by creating irregularities on the implant surface in order to increase the surface roughness in comparison to an untreated surface. It is believed that an increased surface roughness, which gives a larger contact and attachment area between the implant and the bone tissue, provides a better mechanical retention and strength between implant and bone. It is well-known within the art that a surface roughness can be provided by, for example, plasma spraying, blasting or acid etching.
Furthermore, it is known that osteoblasts, i.e, bone-forming cells, sense and react to multiple chemical and physical features of the underlying surface. Formation of bone at an implant surface requires the differentiation of precursor cells into secretory osteoblasts to produce unmineralised extracellular matrix (ECM), and the subsequent calcification of this matrix, as described in for instance Anselme K, “Osteoblast adhesion on biomaterials”, Biomaterials 21, 667-681 (2000).
Alteration of the chemical properties of the implant surface has frequently been used for achieving a better attachment of the implant to the bone tissue. Several methods involve the application of a layer of ceramic material, such as hydroxyapatite, on the implant surface in order to improve the bonding of the implant to bone since hydroxyapatite is chemically related to bone. U.S. Pat. No. 7,169,317 (Beaty) discloses a method for preparing the surface of a bone implant which comprises the removal of the native oxide from the implant surface, acid etching or otherwise treating the resulting implant surface to produce a substantially uniform surface roughness, and depositing discrete particles of a bone-growth enhancing material such as hydroxyapatite, bone minerals and bone morphogenic proteins thereon. The etching and deposition steps are preferably performed in the absence of unreacted oxygen by using an inert atmosphere.
A common disadvantage with coatings comprising hydroxyapatite is, however, that they may be brittle and may flake or break off from the implant surface due to a stronger bond being formed between the bone and coating than between the coating and the implant, which may lead to an ultimate failure of the implant. Regarding the use of protein coatings, there are additional aspects to consider. Due to the chemical nature of proteins, a surface having a protein coating may require specific sterilisation and storage conditions in order to maintain its biological activity. In addition, host tissue response (e.g. immunological response) to biomolecules such as proteins may be unpredictable. Another disadvantage of the method of U.S. Pat. No. 7,169,317 is the requirement for a surface free of oxide, considering that working in an inert atmosphere is inconvenient and requires specialized equipment.
US 2007/01100890 and related applications US 2007/0112353 and WO 2007/059038 (Berckmans III et al) aim at solving the problem of poor adherence of a ceramic coating to the implant and disclose a method of depositing discrete nanoparticles on a roughened implant surface through a process of exposing the implant surface to a solution comprising 2-methoxyethanol solvent and hydroxyapatite (HA) nanocrystals, e.g. in the form of a colloid. The HA nanocrystals are deposited to form a nanostructure which is intended to promote the osseointegration of the implant. However, one negative aspect of this method is the formulation of the nanocrystal-containing composition requiring organic solvents, which may be undesirable due to the risk of organic contamination of the surface, and several processing steps using advanced equipment. The deposition is performed at room temperature, requiring incubation times of 1 to 4 hours.
The roughness of an implant surface has been shown to affect cell proliferation and also the local production of growth factors by the cells around an implant. In vitro studies of human osteoblasts have shown that surfaces of increased microscale roughness resulted in a reduced number of cells, lower cell proliferation and increased matrix production, compared to smoother surfaces (Martin J Y et al., Proliferation, differentiation, and protein synthesis of human osteoblast-like cells (MG63) cultured on previously used titanium surfaces, Clin Oral Implants Res, March 7(1), 27-37, 1996). Yet other studies have shown that surface roughness enhances cell differentiation, while reducing cell proliferation (Kieswetter K, Schwartz Z, Hummert T W, Cochran D L, Simpson J, Dean D D, Boyan B D, “Surface roughness modulates the local production of growth factors and cytokines by osteoblast-like MG-63 cells”, J Biomed Mater Res, September, 32(1), 55-63, 1996). Increased cell differentiation implies a potentially improved rate of bone formation.
Recently, the modulation of adhesive capabilities of cells have advanced from micro to nanopatterning techniques. It is believed that cell function may be regulated by nanostructural physical signals by stimulating integrin-mediated focal adhesion and intracellular signaling in anchorage-dependent cell function (Bershadsky A, Kozlov M, and Geiger B, “Adhesion-mediated mechanosensitivity: a time to experiment, and a time to theorize”, Curr Opin Cell Biol, 18(5), 472-81, 2006).
EP 1440669B1 and related US 2004/0153154 A1 (Dinkelacker) disclose a bone implant having a surface which is reshaped to comprise a microstructure for anchoring the implant in the cell area. The microstructure, which is provided in the form of a cover layer applied on a previously roughened surface, comprises an array of densely packed rounded domes separated by rounded lacunae, the dimensions of the microstructure being approximately the same order of magnitude as the dimensions of the cells. The microstructural cover layer may be applied e.g. by sputtering. Further, a nano-structure, also obtained by sputtering, comprised of rounded domes separated by rounded lacunae is provided on the microstructure, wherein the dimensions of the nanostructure is approximately one decimal order of magnitude smaller than the corresponding dimensions of the microstructure. Again, however, there are potential problems with the stability of the cover layer and the integrity of the attachment between the cover layer and the implant body. Another technique for creating a desirable surface roughness is disclosed in EP 1 449 544 A1 (Wen et al) which provides a method for providing a metallic orthopaedic implant with a micrometre- or nanometre-scale surface roughness, while maintaining the structural integrity of the implant. In this method, an implant having metallic elements adhered to the implant surface, thus defining a porous surface geometry, is etched to produce a micrometre- or nanometre-scale surface roughness. For example, the metallic elements are metallic beads having a size from about 40 μm to several mm. However, this method is rather laborious and requires the use of advanced technical equipment, as the metallic elements are applied by a coating technique followed by sintering to fuse the elements to the implant surface and to each other. Consequently, the method is also expensive.
In brief, although there are today many existing techniques for improving the osseointegration of an implant, these methods generally suffer from drawbacks in respect of processability, cost-efficiency and biological effect and stability after implantation. Thus, there is a need in the art for improvement in the production of implants which have properties which even further promote osseointegration.